Volume 5 Supplement 1

2nd International Conference of cGMP Generators, Effectors and Therapeutic Implications

Open Access

Myocyte-specific overexpression of NOS3 prevents endotoxin-induced myocardial dysfunction in mice

  • Emmanuel Buys1Email author,
  • Fumito Ichinose1,
  • John G Morgan1,
  • Marielle Scherrer-Crosbie1 and
  • Kenneth D Bloch1
BMC Pharmacology20055(Suppl 1):P7

https://doi.org/10.1186/1471-2210-5-S1-P7

Published: 16 June 2005

Endotoxemia can cause profound myocardial dysfunction contributing to hypotension and shock. Overproduction of nitric oxide (NO) has been implicated as a cause of the myocardial dysfunction of sepsis. Here, we tested the hypothesis that myocyte-specific overexpression of NO synthase 3 (NOS3) can prevent cardiac dysfunction in endotoxin-challenged mice.

Echocardiographic measurements were obtained before and 4 and 7 h after intraperitoneal challenge with endotoxin (Escherichia coli 0111:B4 lipopolysaccaride 50 mg/kg) in wild-type C57BL6 mice (WT) and WT mice with myocyte-specific overexpression of NOS3 (TG), using a 13-MHz ultrasound probe (Sequoia, Acuson, Mountain View, CA). Invasive measurements of LV pressure and volume were obtained with a 1.4F pressure-volume catheter (SPR-839, Millar Instruments, Houston TX) (7 h after challenge with endotoxin or saline).

At baseline, WT and TG mice had comparable measures of LV function. However, as assessed by echocardiography, the endotoxin-induced decrease in LV fractional shortening was attenuated in TG mice (from 54 ± 1 to 40 ± 1%) as compared to WT mice (from 56 ± 1 to 31 ± 2%). Invasive hemodynamics revealed that, compared to saline-challenged mice, dP/dtmax and cardiac output (CO) were markedly impaired in WT but not in TG 7 h after endotoxin challenge (Table 1).
Table 1

Cardiac function at baseline and 7 h after endotoxin-challenge in WT and TG mice

  

dP/dtmax (mmHg/s)

CO (mL/min)

PMXEDV (mmHg/s)

dP/dtmax/IP (s-1)

Ees (mmHg/μL)

WT

baseline

15124 ± 1087

14.5 ± 1.9

50 ± 3

287 ± 12

11 ± 2

 

7h endotoxin

10024 ± 609*

6.1 ± 0.9*

31 ± 5*

161 ± 18*

3 ± 1*

TG

baseline

14562 ± 1491

15.6 ± 2.7

43 ± 2

255 ± 16

11 ± 4

 

7h endotoxin

15354 ± 495#

15.7 ± 0.7#

52 ± 5

228 ± 9

12 ± 2#

*P < 0.05 vs baseline, #P < 0.05 vs WT

Myocyte-specific overexpression of NOS3 prevented endotoxin-induced reduction of minimally load-independent measures of LV function, including maximal power divided by end-diastolic volume (PMXEDV), dP/dtmax divided by instantaneous pressure (dP/dtmax/IP) and LV end-systolic elastance (Ees).

These results suggest that myocyte-specific overexpression of NOS3 confers protection against endotoxin-induced myocardial dysfunction.

Authors’ Affiliations

(1)
Cardiovascular Research Center, Massachusetts General Hospital

Copyright

© BioMed Central Ltd 2005

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